1. Field of the Invention
The present invention relates to the fields of genetics and molecular biology. More particular the invention relates to the identification of a gene that is involved in Bardet-Biedl Syndrome (BBS), designated here as BBS1. Defects in this gene are associated with a variety of clinical symptoms including diabetes, hypogonadism, renal cancer and other renal defects, retinopathy, limb deformity or polydactyly, mental retardation and obesity. The invention further provides methods of screening for therapeutic compositions.
2. Description of Related Art
Bardet-Biedl Syndrome (BBS) is a rare, autosomal recessive disorder characterized by obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism (Bardet, 1920; Biedl, 1922; Solis-Cohen and Weiss, 1924; Green et al, 1989). Patients with BBS are also at increased risk for diabetes mellitus, hypertension and congenital heart disease (Green et al., 1989; Harnett et al., 1988; Elbedour et al., 1994). A high frequency of renal abnormalities is also associated with this disorder. The mental retardation is often mild. Obesity begins early in infancy, and complications of obesity including diabetes mellitus and hypertension occur later in life. The associated retinal degeneration is usually severe and most patients become blind prior to 20 years of age. A recent report also provides evidence of an increased incidence of renal cell carcinoma (kidney cancer) as well as kidney malformations in BBS subjects.
The incidence of BBS varies between populations. A relatively high incidence of BBS is found in the mixed Arab populations of Kuwait and the Bedouin tribes throughout the Middle East, most likely due to the high rate of consanguinity in these populations. A relatively high frequency of BBS has also been reported in New Foundland.
BBS has been shown to display a remarkable degree of non-allelic genetic heterogeneity. The disorder was first shown to be genetically heterogenous based on mapping studies performed in large inbred Bedouin kindreds from Israel. The large number of traditional consanguineous marriages within these groups make it possible to identify inbred kindreds with multiple affected individuals that are large enough for independent linkage analysis.
Once thought to be a homogeneous autosomal recessive disorder, BBS is now known to map to at least six loci: 11q13 (BBS1), 16q21 (BBS2), 3p13-p12 (BBS3), 15q22.3-q23 (BBS4), 2q31 (BBS5), and 20p12 (BBS6) (Kwitck-Black et al, 1993; Leppert et al., 1994; Sheffield et al., 1994; Carmi et al., 1995; Young et al., 1999; Slavotinek et al., 2000; Katsanis et al., 2000). There has been considerable interest in identifying the genes that cause BBS because some of the components of the phenotype are common. The first BBS gene (MKKS) was identified independently by two groups that hypothesized that mutations in the gene causing McKusick-Kaufman syndome (MKS) could also cause BBS. MKS is an autosomal recessive disorder characterized by post-axial polydactyly, as well as genital and cardiac anomalies. Mutations in the MKKS gene, a putative chaperonin gene, appear to account for approximately 10% of BBS cases. The mechanism by which mutations in the MKKS gene cause BBS has not been determined.
BBS6 was shown to be caused by mutations in the MKKS gene (Slavotinek et al., 2000; Katsanis et al., 2000), mutations which also cause McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly, and congenital heart defects) (Robinow and Shaw, 1979; Stone et al., 2000). In addition, the inventors recently used positional cloning to identify the genes causing BBS2 (Nishimura et al., 2001) and BBS4 (Mykytyn et al, 2001, and U.S. Ser. No. 60/281,487 filed Apr. 3, 2001). The BBS6 protein has similarity to a T. acidophilum chaperonin (Stone et al, 2000), whereas BBS2 and BBS4 have no significant similarity to chaperoning, nor other known protein families. Recently, it has been suggested that three mutant alleles (two at one locus, and a third at a second locus) may be required for manifestation of BBS (triallelic inheritance) (Katsanis et al., 2001). A seventh BBS locus has been postulated based on the fact that a few small BBS pedigrees do not appear to map to any of the known loci.
Interest in the identification of genes causing BBS stem from the pleiotrophic nature of the disorder, and the fact that identification of BBS genes may provide important insight into biochemical and developmental pathways involved in common complex disorders including obesity and diabetes mellitus.